Malaria is a leading cause of human death and illness, causing each year 400-600 million cases of clinical malaria and 2-3 million deaths. Transmission of malaria is dependent upon successful completion of parasite development in the mosquito. A key step in this process is sporozoite invasion of the mosquito salivary gland. The hypothesis of this research project is that Plasmodium falciparum sporozoite invasion of anopheline salivary glands requires the ligand MAEBL to recognize specific salivary gland receptors. MAEBL is a paralogue of erythrocyte binding proteins known to be essential for merozoite invasion of erythrocytes. We predict that the function of MAEBL in sporozoites requires post-translational processing and distribution to the sporozoite surface prior to invasion and release from the surface during entry into the salivary glands. We expect that receptors recognized by MAEBL are specifically located on the distal lateral lobes of the salivary glands. Our hypothesis is based upon the following observations. First, targeted disruption of the P. berghei MAEBL produced sporozoites that could not attach to or invade mosquito salivary glands. Second, the full-length form of MAEBL expressed during oocyst development is present only as lower molecular weight forms in mature midgut sporozoites. Third, sporozoites attach to and preferentially infect the distal lateral lobes of the female salivary glands in areas that have region- specific surface molecules. Based on these observations, the primary aims of my application are to determine what is the functional form of MAEBL, when midgut sporozoites invade the salivary glands, and what is the role of MAEBL in this invasion process. In addition, we will seek to identify other midgut sporozoite molecules that may have a role in salivary gland invasion. The long-term goal of this research is to better understand the biology of malaria sporozoites in mosquitoes to enhance effectiveness of vector-based anti-malarial intervention.